Romiplostim for chemotherapy-induced thrombocytopenia: Efficacy and safety of extended use
Research and practice in thrombosis and haemostasis. 2022;6(3):e12701
BACKGROUND Chemotherapy-induced thrombocytopenia (CIT) is common during treatment with antineoplastic therapies and may adversely impact chemotherapy dose intensity. There is no approved therapy for CIT. In our recent phase II randomized study, romiplostim led to correction of platelet counts in 85% of treated patients and allowed resumption of chemotherapy, with low rates of recurrent CIT in the first two cycles or 8 weeks of chemotherapy. However, there is a lack of long-term data on the efficacy and safety of romiplostim in CIT. OBJECTIVES To analyze efficacy and safety of romiplostim in the patients in the phase 2 study, who received romiplostim for ≥1 year. PATIENTS/METHODS Twenty-one patients remained on romiplostim for ≥1 year. We analyzed the effect of romiplostim on platelet counts, absolute neutrophil counts, and hemoglobin, as well as impact on ongoing chemotherapy. We also tracked venous or arterial thrombotic events. RESULTS During the study period, romiplostim was effective in preventing reduction of chemotherapy dose intensity due to CIT. Fourteen of the 20 (70%) analyzable patients experienced no episode of CIT, 4 subjects experienced a single chemotherapy dose delay due CIT, and 2 patients required a chemotherapy dose reduction. Platelet counts were preserved throughout the duration of the extension analysis. One patient experienced a proximal deep vein thrombosis, and one patient experienced multiple tumor-related ischemic events. CONCLUSIONS Long-term use of romiplostim for treatment of CIT was effective and safe, with no evidence of resistance or increased risk of thrombosis.
Efficacy of UVC-treated, pathogen-reduced platelets versus untreated platelets: a randomized controlled non-inferiority trial
Pathogen reduction (PR) technologies for blood components have been established to reduce the residual risk of known and emerging infectious agents. THERAFLEX UVPlatelets, a novel UVC light-based PR technology for platelet concentrates, works without photoactive substances. This randomized, controlled, double-blind, multicenter, noninferiority trial was designed to compare the efficacy and safety of UVC-treated platelets to that of untreated platelets in thrombocytopenic patients with hematologic-oncologic diseases. Primary objective was to determine non-inferiority of UVC-treated platelets, assessed by the 1-hour corrected count increment (CCI) in up to eight per-protocol platelet transfusion episodes. Analysis of the 171 eligible patients showed that the defined non-inferiority margin of 30% of UVC-treated platelets was narrowly missed as the mean differences in 1-hour CCI between standard platelets versus UVC-treated platelets for intention-to-treat and perprotocol analyses were 18.2% (95% confidence interval [CI]: 6.4%; 30.1) and 18.7% (95% CI: 6.3%; 31.1%), respectively. In comparison to the control, the UVC group had a 19.2% lower mean 24-hour CCI and was treated with an about 25% higher number of platelet units, but the average number of days to next platelet transfusion did not differ significantly between both treatment groups. The frequency of low-grade adverse events was slightly higher in the UVC group and the frequencies of refractoriness to platelet transfusion, platelet alloimmunization, severe bleeding events, and red blood cell transfusions were comparable between groups. Our study suggests that transfusion of pathogen-reduced platelets produced with the UVC technology is safe but non-inferiority was not demonstrated. (The German Clinical Trials Register number: DRKS00011156).
Intravenous iron is non-inferior to oral iron regarding cell growth and iron metabolism in colorectal cancer associated with iron-deficiency anaemia
Scientific reports. 2021;11(1):13699
Oral iron promotes intestinal tumourigenesis in animal models. In humans, expression of iron transport proteins are altered in colorectal cancer. This study examined whether the route of iron therapy alters iron transport and tumour growth. Colorectal adenocarcinoma patients with pre-operative iron deficiency anaemia received oral ferrous sulphate (n = 15), or intravenous ferric carboxymaltose (n = 15). Paired (normal and tumour tissues) samples were compared for expression of iron loading, iron transporters, proliferation, apoptosis and Wnt signalling using immunohistochemistry and RT-PCR. Iron loading was increased in tumour and distributed to the stroma in intravenous treatment and to the epithelium in oral treatment. Protein and mRNA expression of proliferation and iron transporters were increased in tumours compared to normal tissues but there were no significant differences between the treatment groups. However, intravenous iron treatment reduced ferritin mRNA levels in tumours and replenished body iron stores. Iron distribution to non-epithelial cells in intravenous iron suggests that iron is less bioavailable to tumour cells. Therefore, intravenous iron may be a better option in the treatment of colorectal cancer patients with iron deficiency anaemia due to its efficiency in replenishing iron levels while its effect on proliferation and iron metabolism is similar to that of oral iron treatment.
A Randomized Controlled Trial of Novel Treatment for Hemorrhagic Radiation Proctitis
Asian Pacific journal of cancer prevention : APJCP. 2020;21(10):2927-2934
BACKGROUND Various methods have been used for treatment of hemorrhagic radiation proctitis (HRP) with variable results. Currently, the preferred treatment is formalin application or endoscopic therapy with argon plasma coagulation. Recently, a novel therapy with colonic water irrigation and oral antibiotics showed promising results and more effective compared to 4% formalin application for HRP. The study objective is to compare the effect of water irrigation and oral antibiotics versus 4% formalin application in improving per rectal bleeding due to HRP and related symptoms such as diarrhoea, tenesmus, stool frequency, stool urgency and endoscopic findings. METHODS We conducted a study on 34 patients with HRP and randomly assigned the patients to two treatment arm groups (n=17). The formalin group underwent 4% formalin dab and another session 4 weeks later. The irrigation group self-administered daily rectal irrigation at home for 8 weeks and consumed oral metronidazole and ciprofloxacin during the first one week. We measured the patients' symptoms and endoscopic findings before and after total of 8 weeks of treatment in both groups. RESULTS Our study showed that HRP patients had reduced per rectal bleeding (p = 0.003) in formalin group, whereas irrigation group showed reduced diarrhoea (p=0.018) and tenesmus (p=0.024) symptoms. The comparison between the two treatment arms showed that irrigation technique was better than formalin technique for tenesmus (p=0.043) symptom only. CONCLUSION This novel treatment showed benefit in treating HRP. It could be a new treatment option which is safe and conveniently self-administered at home or used as a combination with other therapies to improve the treatment outcome for HRP.
A Randomized, Double-Blind, Placebo-Controlled, Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin alfa for Chemotherapy-Induced Anemia in Patients With Advanced Non-Small Cell Lung Cancer
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2019
INTRODUCTION This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with non-small cell lung cancer (NSCLC) treated to a 12.0-g/dL hemoglobin (Hb) ceiling. METHODS Adults with stage IV NSCLC expected to receive ≥2 cycles of myelosuppressive chemotherapy and Hb≤11.0 g/dL were randomized 2:1 to blinded 500 mug darbepoetin alfa or placebo Q3W. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] <1.15). Secondary endpoints were PFS and incidence of transfusions or Hb≤8.0 g/dL from week 5 to end of the efficacy treatment period (EOETP). RESULTS The primary analysis set included 2516 patients: 1680 randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR=0.92; 95%CI, 0.831.01) and PFS (stratified HR=0.95; 95%CI, 0.871.04). Darbepoetin alfa was superior to placebo for transfusion or Hb ≤8.0 g/dL from week 5 to EOETP (stratified OR=0.70; 95%CI, 0.570.86; P<.001). Objective tumor response was similar between the arms (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events (AEs) was 31.1% in both arms. No unexpected AEs were observed. CONCLUSIONS Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb≤8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.
Routine Prophylactic Endoscopic Clipping Is Not Efficacious in the Prevention of Delayed Post-Polypectomy Bleeding: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Journal of the Canadian Association of Gastroenterology. 2019;2(3):105-117
Background and Aims: Colorectal cancer (CRC) can be prevented through colonoscopic polypectomy, but this exposes patients to risks, including delayed post-polypectomy bleeding (DPPB). Endoscopists increasingly use clips prophylactically with the aim of preventing DPPB. However, clips are costly, and data to support their efficacy in this context are inconsistent. We performed a systematic review and meta-analysis of randomized controlled trials to assess the efficacy of prophylactic clipping for preventing DPPB. Methods: We searched electronic databases and other relevant sources for randomized controlled trials assessing the efficacy of prophylactic clipping versus no clipping for the prevention of DPPB. Pooled relative risks were determined using a fixed-effects model. Subgroup analyses were also performed. Results: A total of 2305 citations were initially screened. Seven randomized controlled trials satisfied all criteria for inclusion. The quality of included studies was generally low to moderate. A total of 2851 patients underwent 5405 polypectomies. Delayed post-polypectomy bleeding occurred at an overall pooled rate of 2.5%. No overall benefit of clipping for preventing DPPB was observed, with a pooled relative risk of 0.86 (95% confidence interval [CI], 0.55 to 1.36). No significant patient or polyp factors predicting DPPB were found through subgroup analyses. No publication bias was identified. Conclusions: Randomized trials to date do not demonstrate a protective effect of prophylactic clipping for the prevention of DPPB, and therefore, the practice of routine prophylactic clipping appears unjustified. Additional high quality randomized trials are required to identify higher-risk groups that may benefit from prophylactic clipping.
Efficacy and safety of IV ferumoxytol for iron deficiency anemia in patients with cancer
Journal of Blood Medicine. 2017;8:199-209.
Purpose: Iron deficiency anemia (IDA) is common in cancer patients due to blood loss and inflammation. Many do not tolerate oral iron or adequately respond. Intravenous (IV) iron is commonly used as an adjunct to erythropoiesis-stimulating agents; data on the use of IV iron monotherapy in these patients are limited. This study aimed to evaluate IV ferumoxytol for the treatment of cancer patients with IDA with a history of unsatisfactory oral iron therapy or in whom oral iron could not be used. Patients and methods: This post hoc analysis of pooled data from two multicenter, randomized, controlled, Phase III trials evaluating IV ferumoxytol (510 mg x2) vs placebo or iron sucrose (200 mg x5) included a subgroup of 98 patients with cancer that the investigator identified as the primary cause of their IDA, or with cancer whose IDA was attributed to another comorbid condition (ferumoxytol, n=75; iron sucrose, n=13; placebo, n=10). Gastrointestinal cancers were most common (42), followed by breast (14), cervix (ten), and lung (nine). The primary endpoint was the mean change in hemoglobin (Hgb) from baseline to week 5. Results: At week 5, both ferumoxytol and iron sucrose produced significant increases in Hgb from baseline (1.8 g/dL [P<0.0001] and 1.9 g/dL [P=0.002], respectively). During the studies, 45 patients received chemotherapy, 19 with platinum-based regimens. Erythropoiesis-stimulating agent doses were neither increased >20% nor initiated in any treatment group. Overall rates of adverse events and serious adverse events in the cancer subgroup mirrored those in the overall study population. Conclusion: Monotherapy with IV iron appears to be an effective option for cancer patients with IDA who do not respond to or cannot tolerate oral iron therapy.
Oral sucrosomial iron versus intravenous iron in anemic cancer patients without iron deficiency receiving darbepoetin alfa: a pilot study
Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer. 2017;25((9):):2779-2786
PURPOSE Erythropoiesis-stimulating agents (ESAs) are often used in treatment of patients with chemotherapy-induced anemia. Many studies have demonstrated an improved hemoglobin (Hb) response when ESA is combined with intravenous iron supplementation and a higher effectiveness of intravenous iron over traditional oral iron formulations. A new formulation of oral sucrosomial iron featuring an increased bioavailability compared to traditional oral formulations has recently become available and could provide a valid alternative to those by intravenous (IV) route. Our study evaluated the performance of sucrosomial iron versus intravenous iron in increasing hemoglobin in anemic cancer patients receiving chemotherapy and darbepoetin alfa, as well as safety, need of transfusion, and quality of life (QoL). MATERIALS AND METHODS The present study considered a cohort of 64 patients with chemotherapy-related anemia (Hb >8 g/dL <10 g/dL) and no absolute or functional iron deficiency, scheduled to receive chemotherapy and darbepoetin. All patients received darbepoetin alfa 500 mcg once every 3 weeks and were randomly assigned to receive 8 weeks of IV ferric gluconate 125 mg weekly or oral sucrosomial iron 30 mg daily. The primary endpoint was to demonstrate the performance of oral sucrosomial iron in improving Hb response, compared to intravenous iron. The Hb response was defined as the Hb increase ≥2 g/dL from baseline or the attainment Hb ≥ 12 g/dL. RESULTS There was no difference in the Hb response rate between the two treatment arms. Seventy one percent of patients treated with IV iron achieved an erythropoietic response, compared to 70% of patients treated with oral iron. By conventional criteria, this difference is considered to be not statistically significant. There were also no differences in the proportion of patients requiring red blood cell transfusions and changes in QoL. Sucrosomial oral iron was better tolerated. CONCLUSION In cancer patients with chemotherapy-related anemia receiving darbepoetin alfa, sucrosomial oral iron provides similar increase in Hb levels and Hb response, with higher tolerability without the risks or side effects of IV iron.
Lessons from the past: long-term safety and survival outcomes of a prematurely terminated randomized controlled trial on prophylactic vs. hemoglobin-based administration of erythropoiesis-stimulating agents in patients with chemotherapy-induced anemia
Molecular and Clinical Oncology. 2016;4((2)):211-220.
Prophylactic erythropoiesis-stimulating agent (ESA) administration for chemotherapy-induced anemia (CIA) is not supported by current guidelines. Long-term follow-up of patients WHO had been treated with ESA for CIA in the past may provide useful information. In 2002, we undertook a prospective, randomized phase III trial of prophylactic vs. hemoglobin (Hb)-based (threshold: 11 mg/dl) ESA administration in patients with solid tumors and CIA. ESA administration FOR CIA was permanently suspended in 2007 in view of published data at that time, while patient surveillance continued. Among 630 evaluable patients, 38.6% were male, 50.9% had advanced cancer at diagnosis, 40.6% had Hb levels <12 mg/dl at baseline and 47.9% received ESA prophylactically (1:1 randomization). The major tumor types included colorectal (36.0%), breast (20.6%), non-prostate genitourinary (11.0%) and lung CANCER (8.4%). After a median follow-up of 85.4 months, 358 patients had relapsed and 380 had succumbed to the disease. Patients in the prophylactic ESA group (GROUP A; experimental arm), as compared with those in the Hb-based group (GROUP B; iron supplementation alone), exhibited A significantly more prominent increase in median Hb levels, particularly in the subset of patients with non-metastatic disease (two-sided P<0.01) among patients receiving chemotherapy for advanced cancer, those who received ESAs prophylactically exhibited a lower incidence of CIA (all grades: P=0.014, grades 3-4: P=0.034) and fatigue (all grades: P<0.001, grades 3-4: P=0.055), but a higher rate of a composite outcome encompassing all thrombosis-related events (all grades: P=0.043, grades 3-4: P=0.099). These differences were less prominent in the group of patients who received adjuvant treatment. There were no significant differences in overall mortality and relapse/progression rates between the two groups. therefore, prophylactic, compared with Hb-based, administration of ESAs for CIA in patients with solid tumors, was found to be associated with a significantly lower incidence of anemia and fatigue, but with a marginally higher rate of thrombosis-related adverse events, particularly in patients receiving first-line chemotherapy for advanced cancer.
A randomized, noninferiority trial of intravenous iron isomaltoside versus oral iron sulfate in patients with nonmyeloid malignancies and anemia receiving chemotherapy, the PROFOUND trial
STUDY OBJECTIVE A safe alternative to erythropoiesis-stimulating agents to treat anemia is warranted in patients with cancer and anemia; thus, the objective of this trial was to compare the efficacy and safety of intravenous (IV) iron isomaltoside with oral iron in patients with cancer and anemia by testing noninferiority of IV versus oral iron . DESIGN Phase III, prospective, open-label, comparative, randomized, noninferiority, multicenter trial. SETTING Forty-seven hospitals or private cancer clinics in Asia, United States, and Europe. PATIENTS Three hundred fifty patients with cancer and anemia. INTERVENTION Patients were randomized in a 2:1 ratio to either intravenous iron isomaltoside or oral iron sulfate. Patients in the iron isomaltoside group were then randomized into an infusion subgroup (single intravenous infusions of a maximum dose of 1000 mg over 15 min) or a bolus injection subgroup (bolus injections of 500 mg over 2 min). MEASUREMENTS AND MAIN RESULTS The primary efficacy outcome was change in hemoglobin concentration from baseline to week 4. Changes in other relevant hematology variables, effect on quality of life, and safety outcomes were also assessed. The primary efficacy outcome was tested for noninferiority whereas the remaining outcomes were tested for superiority. Iron isomaltoside was noninferior to oral iron in change in hemoglobin concentration from baseline to week 4 (difference estimate 0.016, 95% confidence interval -0.26-0.29, p<0.001). A faster onset of the hemoglobin response was observed with infusion of iron isomaltoside (superiority test: p=0.03 at week 1), and a sustained effect on hemoglobin level was shown in both the iron isomaltoside and oral iron treatment groups until week 24. A significant mean decrease in fatigue score was observed from baseline to week 12 in the iron isomaltoside group (p<0.001) but not in the oral iron group (p=0.057).. A higher proportion of patients treated with oral iron experienced adverse drug reactions (18.8% vs 6.6%, p<0.001) and discontinued the trial due to intolerance (8.0% vs 0.9%, p=0.001). Transient hypophosphatemia (phosphate level < 2 mg/dL) was reported at similar low frequencies among the groups: 7.1% in the iron isomaltoside infusion subgroup versus 8.5% in the iron isomaltoside bolus injection subgroup versus 5.4% in the oral iron group. CONCLUSION This trial demonstrated comparable sustained increases in hemoglobin concentration over time with both iron isomaltoside and oral iron. Iron isomaltoside was better tolerated than oral iron, and fatigue was significantly decreased with iron isomaltoside. Low rates of clinically insignificant hypophosphatemia were reported in patients receiving both treatments. This article is protected by copyright. All rights reserved.